Esophageal Squamous Cell Carcinoma
Conditions
Brief summary
A study of tislelizumab (BGB-A317) plus ociperlimab versus tislelizumab plus placebo as second-line treatment in participants with programmed cell death protein-ligand 1 (PD-L1) tumor area positivity (TAP) ≥ 10% unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma.
Interventions
BIOLOGICALTislelizumab
Tislelizumab is a monoclonal antibody formulated for intravenous injection.
BIOLOGICALOciperlimab
Ociperlimab is a monoclonal antibody formulated for intravenous injection.
DRUGPlacebo
Ociperlimab placebo injection is a sterile, preservative-free solution for infusion formulated in the same buffer as ociperlimab active drug.
Sponsors
BeiGene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Histologically confirmed diagnosis of esophageal squamous cell carcinoma (ESCC). 2. Have progressive disease during or after first-line of systemic treatment for unresectable, locally advanced, recurrent or metastatic ESCC. 3. Have measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 4. Have confirmed programmed cell death protein-ligand 1 (PD-L1) tumor area positivity (TAP) ≥ 10% in tumor tissues tested by the central lab. 5. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Key
Exclusion criteria
1. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways. 2. Participants with evidence of fistula (either esophageal/bronchial or esophageal/aorta). 3. Evidence of complete esophageal obstruction not amenable to treatment. 4. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks after intervention). 5. Has received any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin, etc) or any investigational therapies within 14 days or 5 half-lives (whichever is longer) before the first dose of study drug. Or has received palliative radiation treatment or other local regional therapies within 14 days before the first dose of study drug. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Assessed by the Investigator | Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B. | Objective response rate is defined as the percentage of participants who had a best overall response of confirmed complete response (CR) or partial response (PR) assessed by the Investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Response evaluations were performed using computed tomography or magnetic resonance imaging (MRI) approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. Response (CR or PR) must have been confirmed 4 weeks or later after the first response was observed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate Assessed by the Independent Review Committee | Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B. | Objective response rate is defined as the percentage of participants who had a best overall response of confirmed complete response (CR) or partial response (PR) assessed by the Independent Review Committee (IRC) according to RECIST v1.1. Response evaluations were performed using computed tomography or MRI approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. Response (CR or PR) must have been confirmed 4 weeks or later after the first response was observed. |
| Progression-free Survival (PFS) Assessed by the Independent Review Committee | From randomization up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B. | Progression-free survival is defined as the time from the date of randomization to the date of first documentation of progressive disease assessed by the Independent Review Committee per RECIST v1.1, or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Progressive Disease (PD): At least a 20% increase in the size of target lesions with an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions, or the appearance of any new lesions. |
| Progression-free Survival (PFS) Assessed by the Investigator | From randomization to the end of the study, median (range) time on follow-up was 10.0 (0.5 - 29.9) months in Arm A and 7.8 (0.4 - 29.3) months in Arm B. | Progression-free survival is defined as the time from the date of randomization to the date of first documentation of progressive disease assessed by the Investigator per RECIST v1.1, or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Progressive Disease (PD): At least a 20% increase in the size of target lesions with an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions, or the appearance of any new lesions. |
| Duration Of Response (DOR) Assessed by the Independent Review Committee | From randomization up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B. | Duration of response is defined as the time from the first determination of an objective response (CR or PR) until the first documentation of progressive disease as assessed by the Independent Review Committee per RECIST v1.1, or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. |
| Duration Of Response (DOR) Assessed by the Investigator | From randomization to the end of the study, median (range) time on follow-up was 10.0 (0.5 - 29.9) months in Arm A and 7.8 (0.4 - 29.3) months in Arm B. | Duration of response is defined as the time from the first determination of an objective response (CR or PR) until the first documentation of progressive disease as assessed by the Investigator per RECIST v1.1, or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. |
| Overall Survival | From randomization to the end of the study, median (range) time on follow-up was 10.0 (0.5 - 29.9) months in Arm A and 7.8 (0.4 - 29.3) months in Arm B. | Overall survival (OS) is defined as the time from the date of randomization until the date of death due to any cause. Median overall survival was estimated using the Kaplan-Meier method. For participants who were still alive at the end of the trial, OS was censored at the last known alive date or the date of data cutoff, whichever was earlier. |
| Clinical Benefit Rate Assessed by the IRC and the Investigator | Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B. | Clinical benefit rate is defined as the percentage of participants who achieved a confirmed complete response, partial response, or durable stable disease assessed by the IRC and the Investigator per RECIST v1.1. Response evaluations were performed using computed tomography or MRI approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. Durable SD: Stable disease for ≥ 24 weeks. Response (CR or PR) must have been confirmed 4 weeks or later after the first response. |
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Baseline, Cycle 5 Day 1 and Cycle 7 Day 1 (each cycle was 3 weeks) | The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Higher scores in GHS and functional scales indicate better quality of life. |
| Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Baseline, Cycle 5 Day 1 and Cycle 7 Day 1 (each cycle was 3 weeks) | The EORTC-QLQ-OES18 is the specific esophageal symptoms module of the QLQ-C30. QLQ-OES18 is comprised of 18 questions grouped into 4 multi-item subscales: Dysphagia (3 items), Eating (4 items), Reflux (2 items), and Pain (3 items) and 6 single item subscales (saliva swallowing, choking, dry mouth, taste, coughing, and talking). Participants indicate the extent to which they have experienced symptoms on a scale from 1 (Not at all) to 4 (Very much). Scores are calculated and transformed to a scale from 0 to 100; higher scores indicate a higher level of symptomatology or problems. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From first dose of study drug until 30 days after last dose; median duration of treatment was 3.45 months in Tislelizumab + Ociperlimab arm and 2.79 months in the Tislelizumab + Placebo arm. | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drugs, whether related to study drugs or not. An SAE is any untoward medical occurrence that, at any dose: * Resulted in death * Was life-threatening * Required hospitalization or prolongation of existing hospitalization * Resulted in disability/incapacity * Was a congenital anomaly/birth defect * Was considered a significant medical AE by the Investigator based on medical judgement. AEs were considered related to study drugs if there was evidence to suggest a causal relationship. The investigator assessed the severity of each AE reported based upon National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, where ≥ 3 includes severe or medically significant, life-threatening events or death related to AE. Immune-mediated AEs were diagnosed by the investigator. |
| Disease Control Rate Assessed by the IRC And the Investigator | Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B. | Disease Control Rate is defined as the percentage of participants who had confirmed CR, PR, or stable disease (SD) assessed by the IRC and the investigator per RECIST v1.1. Response evaluations were performed using computed tomography or MRI approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. SD: Neither sufficient shrinkage in size of lesions to qualify for PR nor sufficient increase to qualify for PD, and no new lesions. Response (CR or PR) must have been confirmed 4 weeks or later after the first response. |
Countries
China, France, South Korea, Spain, Taiwan, Thailand
Participant flow
Recruitment details
The study was conducted at 52 study centers in 7 countries/regions in Chinese mainland, Chinese Taiwan, South Korea, Thailand, France, Spain, and Russia.
Pre-assignment details
Participants were randomized equally to one of two treatment groups. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS) score (0 versus 1), number of organs with metastases (≤ 1 versus ≥ 2), and region (Asia versus non-Asia).
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Tislelizumab Plus Ociperlimab Participants received 200 mg tislelizumab plus 900 mg ociperlimab intravenously once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first. | 62 |
| Arm B: Tislelizumab Plus Placebo Participants received 200 mg tislelizumab plus placebo intravenously once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first. | 63 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 39 | 36 |
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Study Closed by Sponsor | 20 | 15 |
| Overall Study | Withdrawal by Subject | 2 | 7 |
Baseline characteristics
| Characteristic | Arm A: Tislelizumab Plus Ociperlimab | Arm B: Tislelizumab Plus Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 36 Participants | 58 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 27 Participants | 67 Participants |
| Age, Continuous | 61.4 years STANDARD_DEVIATION 7.31 | 63.6 years STANDARD_DEVIATION 7.33 | 62.5 years STANDARD_DEVIATION 7.38 |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 (Fully active) | 16 Participants | 15 Participants | 31 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (Restricted but ambulatory) | 46 Participants | 48 Participants | 94 Participants |
| Number of Organs With Metastases ≤ 1 organ | 32 Participants | 33 Participants | 65 Participants |
| Number of Organs With Metastases ≥ 2 organs | 30 Participants | 30 Participants | 60 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 56 Participants | 54 Participants | 110 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 5 Participants | 8 Participants |
| Region Asia | 54 Participants | 54 Participants | 108 Participants |
| Region Non-Asia | 8 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 14 Participants |
| Sex: Female, Male Male | 58 Participants | 53 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 39 / 62 | 36 / 63 |
| other Total, other adverse events | 57 / 62 | 54 / 63 |
| serious Total, serious adverse events | 27 / 62 | 28 / 63 |
Outcome results
Primary
Objective Response Rate (ORR) Assessed by the Investigator
Objective response rate is defined as the percentage of participants who had a best overall response of confirmed complete response (CR) or partial response (PR) assessed by the Investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Response evaluations were performed using computed tomography or magnetic resonance imaging (MRI) approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. Response (CR or PR) must have been confirmed 4 weeks or later after the first response was observed.
Time frame: Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B.
Population: The Intent-to-Treat (ITT) Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Objective Response Rate (ORR) Assessed by the Investigator | 30.6 percentage of participants |
| Arm B: Tislelizumab Plus Placebo | Objective Response Rate (ORR) Assessed by the Investigator | 20.6 percentage of participants |
p-value: 0.211495% CI: [-5.4, 25.3]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales
The EORTC-QLQ-OES18 is the specific esophageal symptoms module of the QLQ-C30. QLQ-OES18 is comprised of 18 questions grouped into 4 multi-item subscales: Dysphagia (3 items), Eating (4 items), Reflux (2 items), and Pain (3 items) and 6 single item subscales (saliva swallowing, choking, dry mouth, taste, coughing, and talking). Participants indicate the extent to which they have experienced symptoms on a scale from 1 (Not at all) to 4 (Very much). Scores are calculated and transformed to a scale from 0 to 100; higher scores indicate a higher level of symptomatology or problems.
Time frame: Baseline, Cycle 5 Day 1 and Cycle 7 Day 1 (each cycle was 3 weeks)
Population: Participants in the ITT Analysis Set who completed the EORTC QLQ-OES18 at baseline; participants with available data at baseline and the relevant post-baseline visit are included in the analysis at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Dysphagia: Cycle 5 | -5.9 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Dysphagia: Cycle 7 | -3.5 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Eating: Cycle 5 | -1.6 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Eating: Cycle 7 | -2.8 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Reflux: Cycle 5 | 1.9 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Reflux: Cycle 7 | 2.7 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Pain: Cycle 5 | 0.1 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Pain: Cycle 7 | -2.1 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Pain: Cycle 7 | 3.3 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Dysphagia: Cycle 5 | 4.1 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Reflux: Cycle 5 | -0.4 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Dysphagia: Cycle 7 | 7.3 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Pain: Cycle 5 | -0.7 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Eating: Cycle 5 | -1.3 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Reflux: Cycle 7 | 4.0 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18) Dysphagia, Eating, Reflux and Pain Scales | Eating: Cycle 7 | 6.6 score on a scale |
Comparison: Analysis of Change from Baseline in Dysphagia at Cycle 5. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-21.5, 1.6]
Comparison: Analysis of Change from Baseline in Dysphagia at Cycle 7. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-27.8, 6.3]
Comparison: Analysis of Change from Baseline in Eating at Cycle 5. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-7.3, 6.6]
Comparison: Analysis of Change from Baseline in Eating at Cycle 7. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-18.5, -0.3]
Comparison: Analysis of Change from Baseline in Reflux at Cycle 5. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-6.7, 11.2]
Comparison: Analysis of Change from Baseline in Reflux at Cycle 7. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-11.8, 9]
Comparison: Analysis of Change from Baseline in Pain at Cycle 5. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-7, 8.5]
Comparison: Analysis of Change from Baseline in Pain at Cycle 7. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-12.3, 1.7]
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores
The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Higher scores in GHS and functional scales indicate better quality of life.
Time frame: Baseline, Cycle 5 Day 1 and Cycle 7 Day 1 (each cycle was 3 weeks)
Population: Participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at baseline; participants with available data at baseline and the relevant post-baseline visit are included in the analysis at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Global Health Status/QOL: Cycle 5 | 1.7 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Global Health Status/QOL: Cycle 7 | 0.3 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Physical Functioning: Cycle 5 | -0.5 score on a scale |
| Arm A: Tislelizumab Plus Ociperlimab | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Physical Functioning: Cycle 7 | -4.4 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Physical Functioning: Cycle 7 | -3.9 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Global Health Status/QOL: Cycle 5 | -0.1 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Physical Functioning: Cycle 5 | 1.2 score on a scale |
| Arm B: Tislelizumab Plus Placebo | Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) and Physical Functioning Scores | Global Health Status/QOL: Cycle 7 | -2.8 score on a scale |
Comparison: Analysis of Change from Baseline in Physical Functioning at Cycle 5. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-7.1, 3.7]
Comparison: Analysis of Change from Baseline in Global Health Status/QoL at Cycle 5. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-8.4, 11.9]
Comparison: Analysis of Change from Baseline in Global Health Status/QoL at Cycle 7. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-5, 11.2]
Comparison: Analysis of Change from Baseline in Physical Functioning at Cycle 7. The mixed effect model analysis included the questionnaire score as dependent variable; baseline score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects; and visit as a repeated measure, with an unstructured covariance structure.95% CI: [-10.3, 9.3]
Secondary
Clinical Benefit Rate Assessed by the IRC and the Investigator
Clinical benefit rate is defined as the percentage of participants who achieved a confirmed complete response, partial response, or durable stable disease assessed by the IRC and the Investigator per RECIST v1.1. Response evaluations were performed using computed tomography or MRI approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. Durable SD: Stable disease for ≥ 24 weeks. Response (CR or PR) must have been confirmed 4 weeks or later after the first response.
Time frame: Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B.
Population: The Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Clinical Benefit Rate Assessed by the IRC and the Investigator | Investigator Assessment | 33.9 percentage of participants |
| Arm A: Tislelizumab Plus Ociperlimab | Clinical Benefit Rate Assessed by the IRC and the Investigator | Independent Review Committee | 32.3 percentage of participants |
| Arm B: Tislelizumab Plus Placebo | Clinical Benefit Rate Assessed by the IRC and the Investigator | Investigator Assessment | 30.2 percentage of participants |
| Arm B: Tislelizumab Plus Placebo | Clinical Benefit Rate Assessed by the IRC and the Investigator | Independent Review Committee | 27.0 percentage of participants |
Comparison: Analysis of Clinical Benefit Rate Assessed by the Investigator95% CI: [-12.7, 20.4]
Comparison: Analysis of Clinical Benefit Rate Assessed by the Independent Review Committee95% CI: [-11, 21]
Secondary
Disease Control Rate Assessed by the IRC And the Investigator
Disease Control Rate is defined as the percentage of participants who had confirmed CR, PR, or stable disease (SD) assessed by the IRC and the investigator per RECIST v1.1. Response evaluations were performed using computed tomography or MRI approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. SD: Neither sufficient shrinkage in size of lesions to qualify for PR nor sufficient increase to qualify for PD, and no new lesions. Response (CR or PR) must have been confirmed 4 weeks or later after the first response.
Time frame: Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B.
Population: The Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Disease Control Rate Assessed by the IRC And the Investigator | Investigator assessment | 61.3 percentage of participants |
| Arm A: Tislelizumab Plus Ociperlimab | Disease Control Rate Assessed by the IRC And the Investigator | Independent Review Committee | 64.5 percentage of participants |
| Arm B: Tislelizumab Plus Placebo | Disease Control Rate Assessed by the IRC And the Investigator | Investigator assessment | 58.7 percentage of participants |
| Arm B: Tislelizumab Plus Placebo | Disease Control Rate Assessed by the IRC And the Investigator | Independent Review Committee | 58.7 percentage of participants |
Comparison: Analysis of Disease Control Rate Assessed by the Investigator95% CI: [-14.4, 19.9]
Comparison: Analysis of Disease Control Rate Assessed by the Independent Review Committee95% CI: [-11.7, 21.8]
Secondary
Duration Of Response (DOR) Assessed by the Independent Review Committee
Duration of response is defined as the time from the first determination of an objective response (CR or PR) until the first documentation of progressive disease as assessed by the Independent Review Committee per RECIST v1.1, or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method.
Time frame: From randomization up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B.
Population: Participants in the Intent-to-Treat Analysis Set who had an objective response per IRC assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Duration Of Response (DOR) Assessed by the Independent Review Committee | 14.6 months |
| Arm B: Tislelizumab Plus Placebo | Duration Of Response (DOR) Assessed by the Independent Review Committee | NA months |
Secondary
Duration Of Response (DOR) Assessed by the Investigator
Duration of response is defined as the time from the first determination of an objective response (CR or PR) until the first documentation of progressive disease as assessed by the Investigator per RECIST v1.1, or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method.
Time frame: From randomization to the end of the study, median (range) time on follow-up was 10.0 (0.5 - 29.9) months in Arm A and 7.8 (0.4 - 29.3) months in Arm B.
Population: Participants in the Intent-to-Treat Analysis Set who had an objective response per Investigator assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Duration Of Response (DOR) Assessed by the Investigator | 11.3 months |
| Arm B: Tislelizumab Plus Placebo | Duration Of Response (DOR) Assessed by the Investigator | NA months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drugs, whether related to study drugs or not. An SAE is any untoward medical occurrence that, at any dose: * Resulted in death * Was life-threatening * Required hospitalization or prolongation of existing hospitalization * Resulted in disability/incapacity * Was a congenital anomaly/birth defect * Was considered a significant medical AE by the Investigator based on medical judgement. AEs were considered related to study drugs if there was evidence to suggest a causal relationship. The investigator assessed the severity of each AE reported based upon National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, where ≥ 3 includes severe or medically significant, life-threatening events or death related to AE. Immune-mediated AEs were diagnosed by the investigator.
Time frame: From first dose of study drug until 30 days after last dose; median duration of treatment was 3.45 months in Tislelizumab + Ociperlimab arm and 2.79 months in the Tislelizumab + Placebo arm.
Population: The Safety Analysis Set included all patients who received ≥ 1 dose of any component of study drugs.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAE | 58 Participants |
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE ≥ Grade 3 | 28 Participants |
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious AEs | 27 Participants |
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Related SAEs | 13 Participants |
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs Leading to Treatment Discontinuation | 9 Participants |
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs Leading to Death (Excluding Due to Disease Under Study) | 4 Participants |
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Immune-Mediated AE | 31 Participants |
| Arm A: Tislelizumab Plus Ociperlimab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Immune-Mediated AE ≥ Grade 3 | 8 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Immune-Mediated AE ≥ Grade 3 | 3 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAE | 60 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs Leading to Treatment Discontinuation | 10 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE ≥ Grade 3 | 28 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any Immune-Mediated AE | 21 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious AEs | 28 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs Leading to Death (Excluding Due to Disease Under Study) | 4 Participants |
| Arm B: Tislelizumab Plus Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Related SAEs | 13 Participants |
Secondary
Objective Response Rate Assessed by the Independent Review Committee
Objective response rate is defined as the percentage of participants who had a best overall response of confirmed complete response (CR) or partial response (PR) assessed by the Independent Review Committee (IRC) according to RECIST v1.1. Response evaluations were performed using computed tomography or MRI approximately every 6 weeks for the first 54 weeks and then every 12 weeks thereafter. CR: Disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) \< 10 mm, and no new lesions. PR: At least a 30% decrease in the size of target lesions, with no progression of non-target lesions and no new lesions, or disappearance of target lesions with persistence of 1 or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions. Response (CR or PR) must have been confirmed 4 weeks or later after the first response was observed.
Time frame: Up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B.
Population: The Intent-to-Treat Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Objective Response Rate Assessed by the Independent Review Committee | 32.3 percentage of participants |
| Arm B: Tislelizumab Plus Placebo | Objective Response Rate Assessed by the Independent Review Committee | 25.4 percentage of participants |
95% CI: [-9.2, 22.5]
Secondary
Overall Survival
Overall survival (OS) is defined as the time from the date of randomization until the date of death due to any cause. Median overall survival was estimated using the Kaplan-Meier method. For participants who were still alive at the end of the trial, OS was censored at the last known alive date or the date of data cutoff, whichever was earlier.
Time frame: From randomization to the end of the study, median (range) time on follow-up was 10.0 (0.5 - 29.9) months in Arm A and 7.8 (0.4 - 29.3) months in Arm B.
Population: The Intent-to-Treat Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Overall Survival | 10.2 months |
| Arm B: Tislelizumab Plus Placebo | Overall Survival | 9.3 months |
95% CI: [0.58, 1.45]
Secondary
Progression-free Survival (PFS) Assessed by the Independent Review Committee
Progression-free survival is defined as the time from the date of randomization to the date of first documentation of progressive disease assessed by the Independent Review Committee per RECIST v1.1, or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Progressive Disease (PD): At least a 20% increase in the size of target lesions with an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions, or the appearance of any new lesions.
Time frame: From randomization up to the primary analysis data cutoff date of 01 February 2023; median (range) time on follow-up was 7.4 (0.5 - 20.1) months in Arm A and 6.4 (0.4 - 20.2) months in Arm B.
Population: The Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Progression-free Survival (PFS) Assessed by the Independent Review Committee | 3.6 months |
| Arm B: Tislelizumab Plus Placebo | Progression-free Survival (PFS) Assessed by the Independent Review Committee | 2.8 months |
95% CI: [0.64, 1.59]
Secondary
Progression-free Survival (PFS) Assessed by the Investigator
Progression-free survival is defined as the time from the date of randomization to the date of first documentation of progressive disease assessed by the Investigator per RECIST v1.1, or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. Progressive Disease (PD): At least a 20% increase in the size of target lesions with an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions, or the appearance of any new lesions.
Time frame: From randomization to the end of the study, median (range) time on follow-up was 10.0 (0.5 - 29.9) months in Arm A and 7.8 (0.4 - 29.3) months in Arm B.
Population: The Intent-to-Treat (ITT) Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Tislelizumab Plus Ociperlimab | Progression-free Survival (PFS) Assessed by the Investigator | 3.4 months |
| Arm B: Tislelizumab Plus Placebo | Progression-free Survival (PFS) Assessed by the Investigator | 3.4 months |
95% CI: [0.71, 1.61]